四肢骨肉瘤患者大剂量氨蝶呤化疗63例报告

High dose methotrexate in chemotherapy for osteosarcoma of the extremities: 63 cases report

目的通过总结四肢骨肉瘤化疗的随机对照多中心临床研究中大剂量甲氨蝶呤(high dose methotrexate,HD-MTX)的应用,为临床安全应用HD-MTX提供依据。方法收集2009年2月至2010年12月国内五所医院的63例骨肉瘤患者(分为实验组32例、对照组31例)。对随机对照多中心的研究中的实验组与对照组合并分析,根据实验设计行统一、规范给药并进行血药浓度监测及相应实验室检查,对HD-MTX应用的相关并发症及毒性反应进行了回顾分析。不良反应采用(the national cancer institute common terminology criteria for adverse event,CTCAE)v4.0评分系统评价肝、肾、血液学及黏膜毒性反应等。结果 63例中HD-MTX治疗共计60例,共给药186个周期,平均给药剂量为7.45 g/m2。血药浓度给药后24 h>20μm占27.9%,48 h后占1%。两组总无进展生存率为37.0%(20/54),总生存率为66.7%(36/54)。谷丙转氨酶最大值2133 mmol/L,>800 mmol/L共发生4例次(CTCAE 4度),200~800 mmol/L(CTCAE 3度)发生15例次;肌酐最大值190 mmol/L(CTCAE 2度),肾功能异常4例次(CTCAE 2度)。严重肝损害发生率为4.8%(9/186),严重肾功能损害发生率为2.2%(4/186)。死亡1例,除死亡病例外无不可逆肝肾损害发生。最早出现的不良反应为给药后1~24 h出现皮肤过敏反应,在有记录的病例中发生率为18.8%(6/32),而其余28例中I^II度骨髓抑制发生率为45%,IV度骨髓抑制发生率12%,口腔炎发生率为13.5%。出现过敏反应后的肝肾损害和骨髓抑制并发症的发生率及程度,较没有过敏反应的病例无差别。呕吐、腹胀、腹泻等不同程度胃肠道反应发生率>90%(CTCAE 1~4度)。结论本研究充分地反映了使用HD-MTX的现状,为今后更加合理应用提供了有利的数据支持,也为临床应用的安全性的提高提供了依据。

Objective To provide a basis for the clinical application of high dose methotrexate （ HD-MTX ） through summarizing the effects of HD-MTX and analyzing its safety in a multicenter randomized controlled study on chemotherapy for osteosarcoma of the extremities. Methods The clinical data of 63 patients with osteosarcoma who were admitted by 5 domestic hospitals from February 2009 to December 2010 were collected, including 32 patients in the experimental group and 31 patients in the control group. A combined analysis of the data in both groups was performed in the multicenter randomized controlled study. According to the experimental design, the patients received unified and standardized administration, whose blood concentration was detected, and the corresponding laboratory examination was performed. The complications related to the application of HD-MTX and toxic reactions were retrospectively analyzed. The side effects were evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events （ CTCAE ） v4.0, including the liver, kidney, hematology and mucosal toxicity. Results Sixty of the 63 patients enrolled in this study received HD-MTX, and a total of 186 cycles were administered, with a mean dosage of 7.45 g / m^2. The patients whose blood concentration was 〉20 μm accounted for 27.9% after 24 br of administration, and 1% after 48 hr of administration. The overall disease free survival rate was 37.0% （ 20 / 54 ）, and the overall survival rate was 66.7% （ 36 / 54 ）. The maximum of glutamic-pyruvic transaminase （ GPT ） was 2133 mmol / L, which was 〉800 mmol / L for 4 times （ CTCAE 4 degrees ） and 200-800 mmol / L for 15 times （ CTCAE grade 3 ）. The maximum of creatinine was 190 mmol / L （ CTCAE grade 2 ）. Abnormal renal function was found in 4 cases （ CTCAE grade 2 ）. The occurrence rate of sever liver injuries was 4.8% （ 9 / 186 ）. The occurrence rate of severe renal function damage was 2.2% （ 4 / 186 ）. There was 1 death case. No irreversible damage to the liver or kidney was found. The adverse reaction of cutaneous anaphylaxis at 1-24 hr after the administration was firstly noticed, and the occurrence rate was 18.8% （ 6 / 32 ） among the recorded cases. The occurrence rates of myelosuppression I-II, myelosuppression IV and stomatitis were 45%, 12% and 13.5% in the other 28 cases. There were no significant differences in the occurrence rate or severity of renal and hepatic injuries and myelosuppression between the patients with anaphylaxis and the patients without anaphylaxis. The occurrence rate of gastrointestinal reactions in different degrees such as vomit, abdominal distension and diarrhea was 〉90% （ CTCAE grade 1-4 ）. Conclusions The application status of HD-MTX are summarized thoroughly in this study, which provides scientific data and a strong basis for the reasonability and safety in its clinical aPPlication.